1. Introduction 20642. Synthesis of Magnetic Nanoparticles 20662.1. Classical Synthesis by Coprecipitation 20662.2. Reactions in Constrained Environments 20682.3. Hydrothermal and High-TemperatureReactions20692.4. Sol-Gel Reactions 20702.5. Polyol Methods 20712.6. Flow Injection Syntheses 20712.7. Electrochemical Methods 20712.8. Aerosol/Vapor Methods 20712.9. Sonolysis 20723. Stabilization of Magnetic Particles 20723.1. Monomeric Stabilizers 20723.1.1. Carboxylates 20733.1.2. Phosphates 20733.2. Inorganic Materials 20733.2.1. Silica 20733.2.2. Gold 20743.3. Polymer Stabilizers 20743.3.1. Dextran 20743.3.2. Polyethylene Glycol (PEG) 20753.3.3. Polyvinyl Alcohol (PVA) 20753.3.4. Alginate 20753.3.5. Chitosan 20753.3.6. Other Polymers 20753.4. Other Strategies for Stabilization 20764. Methods of Vectorization of the Particles 20765. Structural and Physicochemical Characterization 20785.1. Size, Polydispersity, Shape, and SurfaceCharacterization20795.2. Structure of Ferro- or FerrimagneticNanoparticles20805.2.1. Ferro- and Ferrimagnetic Nanoparticles 20805.3. Use of Nanoparticles as Contrast Agents forMRI20825.3.1. High Anisotropy Model 20845.3.2. Small Crystal and Low Anisotropy EnergyLimit20855.3.3. Practical Interests of Magnetic NuclearRelaxation for the Characterization ofSuperparamagnetic Colloid20855.3.4. Relaxation of Agglomerated Systems 20856. Applications 20866.1. MRI: Cellular Labeling, Molecular Imaging(Inﬂammation, Apoptose, etc.)20866.2.

Magnetic Iron Oxide Nanoparticles: Synthesis, Stabilization, Vectorization, Physicochemical Characterizations, and Biological Applications

The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours. The importance of integrins in several cell types that affect tumour progression has made them an appealing target for cancer therapy. Integrin antagonists, including the alphavbeta3 and alphavbeta5 inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clinical developments emphasize the need to identify how integrin antagonists influence the tumour and its microenvironment.

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Integrins in cancer: biological implications and therapeutic opportunities

Magnetic Nanoparticles in MR Imaging and Drug Delivery

Biocompatibility, Pharmaceutical and Biomedical Applications L. Harivardhan Reddy,†,‡ Jose ́ L. Arias, Julien Nicolas,† and Patrick Couvreur*,† †Laboratoire de Physico-Chimie, Pharmacotechnie et Biopharmacie, Universite ́ Paris-Sud XI, UMR CNRS 8612, Faculte ́ de Pharmacie, IFR 141, 5 rue Jean-Baptiste Cleḿent, F-92296 Chat̂enay-Malabry, France Departamento de Farmacia y Tecnología Farmaceútica, Facultad de Farmacia, Campus Universitario de Cartuja s/n, Universidad de Granada, 18071 Granada, Spain ‡Pharmaceutical Sciences Department, Sanofi, 13 Quai Jules Guesdes, F-94403 Vitry-sur-Seine, France

Magnetic nanoparticles: design and characterization, toxicity and biocompatibility, pharmaceutical and biomedical applications.

In medicine, nanotechnology has sparked a rapidly growing interest as it promises to solve a number of issues associated with conventional therapeutic agents, including their poor water solubility (at least, for most anticancer drugs), lack of targeting capability, nonspecific distribution, systemic toxicity, and low therapeutic index. Over the past several decades, remarkable progress has been made in the development and application of engineered nanoparticles to treat cancer more effectively. For example, therapeutic agents have been integrated with nanoparticles engineered with optimal sizes, shapes, and surface properties to increase their solubility, prolong their circulation half-life, improve their biodistribution, and reduce their immunogenicity. Nanoparticles and their payloads have also been favorably delivered into tumors by taking advantage of the pathophysiological conditions, such as the enhanced permeability and retention effect, and the spatial variations in the pH value. Additionally, targeting ligands (e.g., small organic molecules, peptides, antibodies, and nucleic acids) have been added to the surface of nanoparticles to specifically target cancerous cells through selective binding to the receptors overexpressed on their surface. Furthermore, it has been demonstrated that multiple types of therapeutic drugs and/or diagnostic agents (e.g., contrast agents) could be delivered through the same carrier to enable combination therapy with a potential to overcome multidrug resistance, and real-time readout on the treatment efficacy. It is anticipated that precisely engineered nanoparticles will emerge as the next-generation platform for cancer therapy and many other biomedical applications.

Engineered Nanoparticles for Drug Delivery in Cancer Therapy

Angiogenesis is essential for the development of malignant tumors and provides important targets for tumor diagnosis and therapy. To noninvasively assess the angiogenic profile of tumors, novel AvB3 integrin–targeted ultrasmall superparamagnetic iron oxide particles (USPIOs) were designed and their specific uptake by endothelial cells was evaluated in vitro and in vivo. USPIOs were coated with 3-aminopropyltrimethoxysilane (APTMS) and conjugated with Arg-Gly-Asp (RGD) peptides. Accumulation in human umbilical vein endothelial cells (HUVECs) was evaluated using Prussian blue staining, transmission electron microscopy, magnetic resonance (MR) imaging, and inductively coupled plasma mass spectrometry. Uptake of RGD-USPIO by HUVECs was significantly increased when compared with unlabeled USPIO and could be competitively inhibited by addition of unbound RGD. The ability of the RGD-USPIO to noninvasively distinguish tumors with high (HaCaT-ras-A-5RT3) and lower (A431) area fractions of AvB3 integrin–positive vessels was evaluated using a 1.5-T MR scanner. Indeed, after RGD-USPIO injection, there was a more pronounced decrease in T2 relaxation times in HaCaT-ras-A5RT3 tumors than in A431 tumors. Furthermore, T2*-weighted images clearly identified the heterogeneous arrangement of vessels with AvB3 integrins in HaCaT-ras-A-5RT3 tumors by an irregular signal intensity decrease. In contrast, in A431 tumors with predominantly small and uniformly distributed vessels, the signal intensity decreased more homogeneously. In summary, RGD-coupled, APTMS-coated USPIOs efficiently label AvB3 integrins expressed on endothelial cells. Furthermore, these molecular MR imaging probes are capable of distinguishing tumors differing in the degree of AvB3 integrin expression and in their angiogenesis profile even when using a clinical 1.5-T MR scanner. [Cancer Res 2007;67(4):1555–62]

https://cancerres.aacrjournals.org/content/canres/67/4/1555.full.pdf

Specific targeting of tumor angiogenesis by RGD-conjugated ultrasmall superparamagnetic iron oxide particles using a clinical 1.5-T magnetic resonance scanner

In this study silica- and alkoxysilane-coated ultrasmall superparamagnetic iron oxide (USPIO) particles were synthesized, and their ability to label immortalized progenitor cells for magnetic resonance imaging (MRI) was compared. USPIO particles were synthesized by coprecipitation of ferric and ferrous salts. Subsequently, the particles were coated with silica, (3-aminopropyl)trimethoxysilane (APTMS), and [N-(2-aminoethyl)-3-aminopropyl]trimethoxysilane (AEAPTMS). The size of the USPIO particles was about 10 nm without a significant increase in diameter after coating. The highest T2 relaxivity was achieved for silica-coated USPIO particles, 339.80 ± 0.22 s-1 mM-1, as compared with APTMS- and AEAPTMS-coated ones, reaching 134.40 ± 0.01 and 84.79 ± 0.02 s-1 mM-1, respectively. No toxic effects on the cells could be detected by trypan blue, TUNEL, and MTS assays. Uptake of USPIO particles was evaluated by Prussian blue staining, transmission electron microscopy, T2-MR relaxometry, and mass spectrometry. It w...

Silica- and Alkoxysilane-Coated Ultrasmall Superparamagnetic Iron Oxide Particles: A Promising Tool To Label Cells for Magnetic Resonance Imaging

Tumor Microenvironment-Responsive Nanohybrid for Hypoxia amelioration with Photodynamic and Near-Infrared II Photothermal Combination Therapy.

Dual-Performance Optimized Silks from Ultra-Low Dose Polymer Dots Feeding and Its Absorption, Distribution and Excretion in the Silkworms

The present invention relates to a contrast agent for magnetic resonance imaging comprising a compound of the formula Pep-L-Im, wherein Pep is a polypeptide molecule selected from the group consisting of (i) polypept ide having an amino acid sequence of NO:1; SEQ ID NO:2; SEQ ID NO:3; SEQ ID NO: 7; SEQ ID NO: 8; SEQ ID NO: 9; or SEQ ID NO: 13; (ii) polypept ide having an amino acid sequence which is at least 80 % identical with one of the amino acid sequences of NO:1; SEQ ID NO:2; SEQ ID NO:3; SEQ ID NO: 7; SEQ ID NO: 8; SEQ ID NO: 9; or SEQ ID NO: 13; and (iii) polypept ide derivative obtained through substitution, addition, inversion and/or deletion of one or two amino acids of the amino acid sequences of NO:1; SEQ ID NO:2; SEQ ID NO:3; SEQ ID NO: 7; SEQ ID NO: 8; SEQ ID NO: 9; or SEQ ID NO: 13, which binds to uPAR; L is a covalent single bond or a spacer; and Im is at least one superparamagnetic iron oxide particle having a coating of an anorganic or organic or anorganic and organic polymer, wherein the coating is covalently attached to L or to Pep, when L is a bond. Another aspect of the present invention is an in-vivo diagnostic method based on magnetic resonance imaging using said contrast agent.

Chunfu Zhang

Papers

Specific targeting of tumor angiogenesis by RGD-conjugated ultrasmall superparamagnetic iron oxide particles using a clinical 1.5-T magnetic resonance scanner

Silica- and Alkoxysilane-Coated Ultrasmall Superparamagnetic Iron Oxide Particles: A Promising Tool To Label Cells for Magnetic Resonance Imaging

Tumor Microenvironment-Responsive Nanohybrid for Hypoxia amelioration with Photodynamic and Near-Infrared II Photothermal Combination Therapy.

Dual-Performance Optimized Silks from Ultra-Low Dose Polymer Dots Feeding and Its Absorption, Distribution and Excretion in the Silkworms

Upar selective contrast agent for magnetic resonance imaging